Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

Abstract

Germline mutations in PTEN, which encodes a widely expressed phosphatase, was mapped to 10q23 and identified as the susceptibility gene for Cowden syndrome, characterized by macrocephaly and high risks of breast, thyroid, and other cancers. The phenotypic spectrum of PTEN mutations expanded to include autism with macrocephaly only 10 years ago. Neurological studies of patients with PTENassociated autism spectrum disorder (ASD) show increases in cortical white matter and a distinctive cognitive profile, including delayed language development with poor working memory and processing speed. Once a germline PTEN mutation is found, and a diagnosis of phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome made, the clinical outlook broadens to include higher lifetime risks for multiple cancers, beginning in childhood with thyroid cancer. First described as a tumor suppressor, PTEN is a major negative regulator of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) signaling pathway-controlling growth, protein synthesis, and proliferation. This canonical function combines with less well-understood mechanisms to influence synaptic plasticity and neuronal cytoarchitecture. Several excellent mouse models of Pten loss or dysfunction link these neural functions to autism-like behavioral abnormalities, such as altered sociability, repetitive behaviors, and phenotypes like anxiety that are often associated with ASD in humans. These models also show the promise of mTOR inhibitors as therapeutic agents capable of reversing phenotypes ranging from overgrowth to low social behavior. Based on these findings, therapeutic options for patients with PTEN hamartoma tumor syndrome and ASD are coming into view, even as new discoveries in PTEN biology add complexity to our understanding of this master regulator.

Characterization of cryptic splicing in germline PTEN intronic variants in Cowden syndrome

“…Cowden syndrome (CS) is an uncommon, but difficult to recognize, disorder that results in hamartomas and an increased risk of breast, thyroid, endometrial, and renal cancers (Ngeow & Eng, ; Tan et al., ). The majority of CS patients have macrocephaly (Mester, Tilot, Rybicki, Frazier, & Eng, ), and there is a subset of patients with autism spectrum disorder and macrocephaly with germline PTEN (MIM# 601728) mutations (Butler et al., ; Tilot, Frazier, & Eng, ). The CS susceptibility locus was initially mapped to 10q23.3 (Nelen et al., ) and 9‐exon PTEN was subsequently identified as the predisposition locus (Li & Sun, ; Liaw et al., ; Lynch et al., ).…”

Autism Spectrum Disorder Associated with Germline Heterozygous PTEN Mutations

“…Initial cases were suggestive of an association (Delatycki et al 2003;Eng 2003) and subsequent small cohort studies identified an enriched number of PTEN mutations in ASD cases with macrocephaly (PTEN-ASD) (Butler et al 2005;Buxbaum et al 2007). Later cohorts with larger samples of individuals with ASD and/or ID (neurodevelopmental delay) found similar proportions of PTEN mutations (Herman et al 2007;Orrico et al 2009;Varga et al 2009;McBride et al 2010;Hobert et al 2014), resulting in a weighted average of 17% of macrocephalic ASD and translating to approximately 2% of all ASD cases (Tilot et al 2015). Approaching ASD prevalence from the PTEN mutation angle, recent case series have suggested that 25%-50% of children with PTEN mutations are identified with ASD (Hansen-Kiss et al 2017;Ciaccio et al 2018).…”

Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies

“…A subset of variants in the PTEN gene, particularly those that alter residues outside of the phosphatase domain and are associated with cancer, may act in a dominant negative fashion [Papa et al, ]. While mouse and in vitro human cell models have demonstrated the efficacy of mTOR inhibitors in reversing part of the phenotypic consequences of PTEN haploinsufficiency, mostly on its canonical effects on cell growth and number [Krymskaya and Goncharova, ; Tilot et al, ], their efficacy on the non‐canonical “moonlighting” functions of PTEN , such as chromatin and transcriptional activity, remains unclear. This has implications for therapeutic outcomes, since inhibiting the effects from excessive PI3K pathway activity may not be sufficient or may not target other aspects of PTEN function that extend beyond the PI3K‐AKT‐mTOR signaling pathway, including its functions in the nucleus.…”